DESCRIPTION (applicant's description):The EGF receptor (EGFR) system is important in the growth and differentiation of epithelial cells. Activation of the EGFR in vivo depends on ligand availability. Epithelial cells typically express several EGFR ligands that are initially synthesized as membrane-anchored precursors that are processed by specific metalloproteases. The distribution and processing of ligands are highly dependent on precursor structure and are regulated by specific signal transduction pathways. The long-term goal of our research is to develop an integrated experimental and mathematical model of ligand regulation in order to understand the relationship between ligand access and biological responses. We hypothesize that the regulated release and redistribution of ligands are part of a system by which cells actively sense their environment. To test this hypothesis, we will systematically modify ligand structure using a domain-swapping strategy to create a series of artificial ligands that display defined differences in their regulated release and access to the EGFR. The ability of these engineered ligands to interact with the EGFR and to induce specific biochemical and biological responses will be quantified. A mathematical model will be developed to integrate information derived from experimental studies of individual ligands. This model will then be used as a tool to develop a unified understanding of the relationship between ligand access and receptor activation. Information obtained from our idealized artificial ligands, will then be used as a reference point from which to study the function of natural ligands. The results of our study should improve our basic understanding of how the EGFR system is regulated in normal epithelium and will help to identify regulatory mechanisms that may fail in cancer and other diseases. In addition, they should provide some general insights into how other growth factor systems are regulated.